The proposed research will examine the influence of social environment on hyperlipidemic, oxidative, and[unreadable] inflammatory mechanisms of atherosclerosis in the Watanabe Heritable Hyperlipidemic rabbit (WHHL).[unreadable] Previous research from our laboratory demonstrated that WHHLs allowed to maintain stable relationships, as[unreadable] opposed to WHHLs housed alone or subjected to unstable relationships, showed a significant decrease in[unreadable] the progression of atherosclerosis. An unstable social environment, characterized by agonistic behavior and[unreadable] emotional stress, was associated with the development of severe atherosclerotic lesions (fibrous caps,[unreadable] necrosis, calcification), whereas individually-caged WHHLs developed extensive lesions that were not as[unreadable] advanced (primarily foam cells and fatty streaks). The individually-caged WHHLs were also behaviorally[unreadable] sedentary, gained more weight, and were hyperinsulinemic relative to the other groups. Taken together,[unreadable] these findings suggest that biobehavioral factors are important in the progression of atherosclerosis, even in[unreadable] a predominantly genetic model of disease. Based on preliminary data, it is hypothesized that social[unreadable] environment differentially modulates inflammatory and oxidative stress mechanisms responsible for disease[unreadable] progression. Hyperlipidemia, which is common to all WHHLs, is viewed as a primary risk factor capable of[unreadable] directly stimulating the formation of vascular foam cells and fatty streaks. Over time, oxidative stress and[unreadable] inflammatory mechanisms are activated, which accelerates progression of disease, leading to more[unreadable] advanced lesions and vulnerable plaque. It is proposed that atherosclerosis in the Stable Social Group[unreadable] progresses slowly due to the antioxidant and anti-inflammatory actions of plasma oxytocin on vascular cells.[unreadable] In the Individually-Caged Group, it is proposed that increased vascular oxidative stress due to behavioral[unreadable] inactivity and hyperinsulinemia leads to rapid development of foamy, fatty lesions in vulnerable regions of the[unreadable] aorta. We hypothesize that the Unstable Social Group develops lesions of similar size and location to the[unreadable] Individually-Caged animals due to the hyperlipidemic mechanisms, however, disease severity progresses[unreadable] more rapidly in the Unstable WHHLs due to chronic activation of the sympathetic nervous system (SNS)[unreadable] which stimulates the release of proinflammatory cytokines and C-reactive protein (CRP). Therefore, the[unreadable] specific aims of the project are: 1.) To assess the influence of plasma oxytocin, as a function of social[unreadable] environment, on vascular oxidative stress, inflammation, and atherosclerosis in the WHHL model, 2.) To[unreadable] measure the effects of NAD(P)H oxidase antagonism, or angiotensin receptor (AT1) antagonism, on the[unreadable] progression of atherosclerosis as a function of social environment, and 3.) To assess the role of[unreadable] proinflammatory cytokines and CRP on disease progression as a function of social environment, and the[unreadable] effects of SNS antagonism on these inflammatory mechanisms.